Steroid hormone receptors, including androgen receptor (AR), glucocorticoid receptor (GR), and the progesterone receptor (PR), require the ordered assembly of various chaperone and co-chaperone proteins in order to reach a functional state. The final stage in the receptor maturation process requires the formation of a multimeric complex consisting of an Hsp90 dimer, p23, and one of several large immunophilins. Previous studies have demonstrated that (i) the large immunophilin, FK506-binding protein 52 (FKBP52), acts to potentiate GR, AR, and PR receptor signaling pathways, and (ii) FKBP52-mediated regulation of receptor function appears to be localized to the receptor hormone binding domain. In cellular studies, FKBP52 has been shown to preferentially regulate GR, AR, and PR receptor-mediated signal transduction (See, for example, Cheung-Flynn et al., Mol. Endocrinol., 19:1654-66 (2005); Riggs et al., EMBO J., 22:1158-67 (2003); Tranguch et al., J. Clin. Invest., 117:1824-34 (2007)). Given its receptor specificity, FKBP52 represents an attractive therapeutic target for the treatment of hormone-dependent diseases.
To date, the only known compounds for inhibition of AR function are related to selective AR modulators that bind to the hormone binding pocket, and are therefore competitive inhibitors of endogenous hormone binding. It has been shown that when certain molecules bind to the binding function 3 (BF3) region of the AR hormone binding domain they can generally inhibit AR function in the 100 μM range. See, Estebanez-Perpina et al., Proc. Natl. Acad. Sci. USA, 104:16074-79 (2007). However, there still exists a need for compounds and formulations for providing selective AR modulators which are not competitive agonists or antagonists to endogenous hormone binding.